Diarylsulfones are known chemotherapeutic agents which are a new class of non-nucleoside reverse transcriptase inhibitors with various structural features responsible for their antiviral activity having been identified.
Variously substituted diaryl sulfones and related derivatives showing activity against immunodeficiency virus (HIV) have been reported in McMahon et al., Antimicrobial Agents and Chemotherapy, 37(4):754-760 (1993), "Diaryl-sulfones, A New Chemical Class of Nonnucleoside Antiviral Inhibitors of Human Immunodeficiency Antiviral inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase". In the reference, substituted diaryl sulfones and related derivatives were found to specifically prevent HIV Type 1 (HIV-1) replication and HIV-1 induced cell killing in vitro. As reported in McMahon et al., 2-nitrophenyl phenylsulfone was found to display high efficacy in protecting human cells in culture from HIV-1 cytopathic effects, as well as inhibition of HIV-1 replication via inhibition of HIV-1 reverse transcriptase. The base structure for compounds tested for biological activity in this reference is as follows: ##STR2##
Buckheit et al., Antiviral Chemistry & Chemotherapy 7(5): 243-252 (1996) reports structure-activity relationship evaluations with several diarylsulfone non-nucleoside reverse transcriptase inhibitors. As set forth in this reference, it was observed that steric properties of various molecules and compound lipophilicity contributed to compound biological activity against HIV-1, with the most active compounds being diarylsulfones having an orthonitro group yielding anti-HIV-1 activity at sub-micromolar concentrations. Further, diarylsulfone compounds were found to exhibit antiviral properties in a manner similar to other members of the class of HIV-1 specific reverse transcriptase inhibitors, as well as synergistic inhibitors of HIV-1 by certain diarylsulfone compounds used in combination with nucleoside analogues AZT, ddI, 3TC, d4T, and protease inhibitor KN1-272.
In Antico et al., Arch. Pharm. (Weinheim) 328, 223-229 (1995), several diarylsulfone compounds were found to be selectively active as anti-HIV-1 agents with the most efficacy shown by 2-nitrophenyl 1-pyrroyl sulfate with a carbethoxy group at the 2 position of pyrrole. In fact, unlike 2-nitrophenyl phenyl sulfone (NPPS), only derivatives bearing a carbethoxy group in the pyrrole ring 2 position were shown to exhibit anti-HIV-1 efficacy. Thus, as reported, in Artico et al., unlike the NPPS diarylsulfone structure, ##STR3## in order to act as an anti-HIV agent, the 2-nitrophenyl 1-pyrryl sulfone skeleton must have the presence of a carbethoxy functional group, such as, ##STR4##
Other references which describe inhibition of HIV reverse transcriptase by sulfones are U.S. Pat. No. 5,308,854 (thiamorpholinyl sulfone) and U.S. Pat. No. 5,565,200 (divinyl sulfone) in which the sulfone group is not a linking group between aryl groups.
Further, U.S. Pat. No. 5,545,750 describes retro-viral protease inhibiting compounds of the formula A--X--B, wherein X can be a sulfone linking group, and in which A and B can be functionalized, cyclic groups which are limited to heterocyclic groups. Bis-(2-phenyl ethyl) sulfone is also discussed in this reference.
U.S. Pat. No. 4,505,929 describes an anti-retroviral-exhibiting compound in which a sulfone group is a linking group between an "R" group which may be a phenyl group and a diphenyl ether group (a sulfone phenyl diphenyl ether).
Additionally, U.S. Pat. No. 5,278,173 discloses the use of diaminodiphenyl sulfone in inhibiting HIV activity in vivo.